1. Field of the Invention
The present invention provides new pharmaceutically active compounds, particularly compounds where a diamino substituted heterocyclic moiety is linked via a methylene group to a substituted aryl group. Preferred compounds of the invention include substituted pyrimidine compounds and can exhibit dihydrofolate reductase (DHFR) inhibition activity.
2. Background
Trimethoprim (1, TMP) and piritrexim (2, PTX) are lipid-soluble antifolates that have been used clinically for the prophylaxis and treatment of Pneumocystis carinii and Toxoplasma gondii infections in patients with AIDS (Klepser, M. E.; Klepser, T. B. Drugs 1997; 53, 40–73). TMP was developed over 40 years ago as an antibacterial drug and continues to be widely prescribed, generally in combination with a sulfonamide such as sulfamethoxazole (this combination, also called co-trimoxazole, is popularly known as Bactrim®). A number of clinical studies evaluating a variety of TMP-sulfa drug combinations for treatment or prevention of life-threatening P. carinii and T. gondii infections in AIDS have been reported in the past decade ((a) Fischl, M. A.; Dickinson, G. M.; La Voie, L. J. Am. Med. Assoc. 1988; 259, 1185–1189; (b) Medina, I.; Mills, J.; Leoung, G.; Hopewell, P. C.; Lee, B.; Modin, G.; Benowitz, N.; Wofsy, C. B. N. Engl. J. Med. 1990; 323, 776–782; (c) Hughes, W.; Leoung, G.; Kramer, F.; Bozzette, S. A.; Safrin, S.; Frame, P.; Clumeck, N.; Mazur, H.; Lancaster, D.; Chan, C.; Lavelle, J.; Rosenstock, J.; Falloon, J.; Feinberg, J.; LaFon, S.; Rogers, M.; Sattler, F. N. Engl. J. Med. 1993; 328, 1521–1527; (d) Safrin, S.; Finkelstein, D. M.; Feinberg, J.; Frame, P.; Simpson, G.; Su, A.; Cheung, T.; Soeiro, R.; Hojczyk, P.; Black J. R. ACTG 108 Study Group, Ann. Intern. Med. 1996; 124, 702–802; (e). Eur J. Clin. Microbiol. Infect. Dis. 1992; 11, 12–130; (f) Podzamczer, D.; Salazar, A.; Jimenez, J.; Consiglio, E.; Santin, M.; Casanova, A.; Rufi, G.; Gudiol, F. Ann. Intern. Med. 1995;122, 755–781; and (g) Antinori, A.; Murri, R.; Ammassari, A.; De Luca, A.; Linzalone, A.; Cingolani, A.; Damiano, F.; Mauro, G.; Vecchiet, J.; Scoppettuolo, G. AIDS 1995; 9, 1343–1350).
Co-trimoxazole is relatively inexpensive, and thus plays an especially important role in controlling AIDS opportunistic infections in economically disadvantaged countries. Initially developed as an anticancer drug, PTX has recently shown some promise against head-and-neck squamous cell carcinoma and bladder carcinomas and has been the subject of one limited clinical study against P. carinii pneumonia in patients with AIDS ((a) Uen, W. C; Huang, A. T.; Mennel, R.; Jones, S. E. Spaulding, M. B.; Killion, K.; Havlin, K.; Keegan, P. Clendeninn, N. J. Cancer 1992; 69, 1008–1011; (b) Schiesel, J. D.; Carabasi, M.; Magill, G.; Casper, E.; Cheng, E.; Marks, L.; Feyzi, J.; Clendeninn, N. J.; Smalley, R. V. Invest. New Drugs 1992; 10, 97–98; (c) Roth B. J. Semin. Oncol. 1996; 23: 633–644; (d) Khorsand, M.; Lange, J.; Feun, L. G.; Clendeninn, N. J.; Collier, M.; Wilding, G. Invest. New Drugs 1997; 15 157–163). Both TMP and PTX have as their target the enzyme dihydrofolate reductase (DHFR), which plays a ubiquitous role in one-carbon metabolism by mediating the biosynthesis of DNA, RNA, and the essential amino acid methionine (Schweitzer, B. I.; Dicker, A. P.; Bertino, J. R. FASEB J. 1990; 4, 2441–2452).

In Kuyper et al., J. Med. Chem. 1985; 28, 303–311, a series of compounds were reported in one of the earliest examples of rational structure-based design of DHFR inhibitors. In a series of trimethoprim analogs where the 3′-OMe group was replaced by O-(ω-carboxyalkyl) substituents having up to six CH2 groups, inhibition assays against E. coli DHFR revealed a progressive decrease in the Ki values from 2.6 nM to 0.035 nM as the number of CH2 groups was increased from 1 to 3, followed by stabilization of the K1 in the 0.025–0.066 nM range as this number was increased from 3 to 6. The highest affinity for E coli DHFR was observed with the O-(5-carboxypentyl) analog 18.

The published literature contains hundreds of mono-, di-, and tricyclic 2,4-diaminopyrimidines that are more potent than trimethoprim, 1, as inhibitors of P. carinii versus rat DHFR, but a careful search reveals only a handful whose selectivity and potency are both greater than those of trimethoprim, 1, (FIG. 1). These include the trimethoprim analog 19 (epiroprim, Ro11-8958), the pyrimethamine analogs 20 and 21, the purine 22, the furo[2,3-d]pyrimidines 23 and 24, and the pteridines 25 and 26. See, for example, (a) Then, R. L.; Hartman, P. G.; Kompis, I.; Stephan-Güldner, M; Stöckel, K. Epiroprim. Drugs Future 1994; 19, 446–449. (b) Chang, H. R.; Arsenijevic D.; Comte, R; Polak, A.; Then, R. L.; Pechere, J. C. Antimicrob. Agents Chemother. 1994; 38, 1803–1807. (c) Martinez, A.; Allegra, C. J.; Kovacs, J. A. Am. J. Trop. Med. Hyg. 1996; 54, 249–252. (d) Locher, H. H.; Schlunegger, H.; Hartman, P. G.; Angehm, P.; Then, R. L. Antimicrob. Agents Chemother. 1996; 40, 1376–1381. (e) Queener, S. F. J. Med. Chem. 1995; 4739–4758. (f) Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. J. Med. Chem. 1996; 39, 1438–1446. (g) Kuyper L. F.; Roth, B.; Baccanari, D. P.; Ferone, R.; Beddell, C. R.; Champness, J. N.; Stammers, D. K.; Dann, J. G.; Norrington, F. E. A.; Baker, D. J.; Goodford, P. J. J. Med. Chem. 1985; 28, 303–311. (h) Stevens, M. F. G.; Phillip, K. S.; Rathbone, D. L.; O'Shea, D. M.; Queener, S. F.; Schwalbe, C. H.; Lambert, P. A. J. Med. Chem. 1997, 40, 1886–1893. (h) Gangjee, A.; Vasudevan, A.; Queener, S. F. J. Med. Chem. 1997, 40, 3032–3039. (i) Gangjee, A.; Guo, X.; Queener, S. F.; Galitsky, N.; Luft, J.; Pangbom, W. J. Med. Chem. 1998; 44, 1263–1271. (j) Piper, J. R.; Johnson, C. A.; Krauth, C. A.; Carter, R. L.; Hosmer, C. A.; Queener, S. F.; Borotz, S. E.; Pfefferkorn, E. R. J. Med. Chem. 1996; 39, 1271–1280. (k) Rosowsky, A.; Cody, V.; Galitsky, N.; Fu, H.; Papoulis, A. T.; Queener, S. F. J. Med. Chem. 1999; 42, 4853–4860.

It would be desirable to have new biologically active DHFR inhibitors, particularly DHFR inhibitors which have selective activity against parasitic DHFR enzymes.